Ultrasound and Photoacoustic Imaging for Enhanced Differential Diagnosis of Rectal Cancer
- Conditions
- Rectal CancerColorectal Cancer
- Interventions
- Device: Photoacoustic imaging, photoacoustic microscopyDevice: Endorectal photoacoustic imaging probe
- Registration Number
- NCT04339374
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
The purpose of this study is to demonstrate the functionality of a novel endorectal photoacoustic ultrasound imaging modality in humans with rectal cancer. The study involves testing a previously developed endorectal device to determine its ability to accurately assess rectal tumor response to preoperative treatment. Investigators hypothesize that a co-registered photoacoustic ultrasound endorectal device can significantly reduce unnecessary surgeries in rectal cancer patients with complete clinical response while maintaining high sensitivity in identifying those with residual cancer.
- Detailed Description
The investigators hypothesize that a co-registered photoacoustic ultrasound endorectal device can significantly reduce unnecessary surgeries in rectal cancer patients with complete clinical response while maintaining high sensitivity in identifying those with residual cancer. The proposed new imaging technique combined with deep-learning algorithms will provide a real-time imaging tool to assist surgeons in predicting the neoadjuvant treatment response of rectal cancer patients. Such a tool will offer sensitive vascular and %sO2 contrast for identifying complete responses, thereby assisting surgeons in significantly improving sensitivity and specificity in surgery recommendations. The study will 1) rigorously validate the technique in a group of LARC patients who will undergo surgical resection of their rectum based on the SOC, and 2) explore the technique's potential in assessing a sub-group of LARC patients through the course of neoadjuvant treatment and in post-treatment surveillance. Successful completion of the project will result in a new imaging tool that can significantly improve the SOC by reducing unnecessary surgery without compromising cancer-related outcomes and thereby lowering morbidity and health care cost.
In this trial, the investigators will recruit patients with rectal cancer who have completed neoadjuvant therapy and will undergo surgery or nonoperative management. Approximately 86 patients will be recruited. The first group of 30 patients (group #1) will be used to train/validate identification algorithm. The second group of 56 patients (group #2) will be used as the testing cohort to train the reader team comprised of 3 surgeons and 1 radiologist. Eligible patients will include those with rectal cancer who received neoadjuvant therapy and were deemed to either have incomplete or indeterminant response based on standard endoscopy and axial imaging with magnetic resonance. PAM/US will be performed before their surgery.
After initial training, the study surgeon will grade the lesion as either PAM/US non-cCR or PAM/US cCR at the time of PAM/US imaging. The study radiologist, blinded from the surgeon's read, will also grade the lesion based on MRI and other clinical information. PAM/US-CNNs provide a real-time imaging tool to assist the reader team in diagnosis. The pathological outcomes of the patients will be assessed based on Tumor Regression Score by standard pathologic evaluation. The sensitivity and specificity of the reader team assisted by PAM/US-CNNs will be obtained from the testing cohort of patients.
The study surgeon will review each patient's record and decide on surgery (clinical non-responders, non-cCR) for two types of patients of 1) those deemed non-cCR based on SOC at the treatment completion; 2) those deemed cCR at the treatment completion, however, later have tumor recurrence based on SOC assessment (non-cCR). PAM/US will be performed before their surgery. After initial training, the study surgeon will grade the lesion as either PAM/US non-cCR or PAM/US cCR at the time of PAM/US imaging. The study radiologist, blinded from the surgeon's read, will also grade the lesion. PAM/US-CNNs provide a real-time imaging tool to assist the reader team in diagnosis. The pathological outcomes of the patients will be assessed based on the Modified Ryan Scheme for Tumor Regression Score. Score 0, No viable cancer cells (pCR); Score 1, Single cells or rare small groups of cancer cells (near pCR); Score 2, Residual cancer with evident tumor regression, but more than single cells or rare small groups of cancer cells; Score 3, Extensive residual cancer with no evident tumor regression. Scores 2 and 3 are considered as non-pCRs. The sensitivity and specificity of the reader team assisted by PAM/US-CNNs will be obtained from the testing cohort of patients. If the methodology is validated from this prospective study, surgeries could be significantly reduced in this group of patients who are pCRs or near pCRs and whose PAM/US imaging scores provided by reader team classify them as responders. The investigators will also correlate MRI/DWI findings with PAM/US and document agreement/discordance with explanations.
As an exploratory part of this trial, a subset of eligible patients of group #2 of will be selected to undergo three serial imaging studies: at pre-treatment, halfway through treatment (after completion of one week of radiation followed by 2 months of chemotherapy), and at treatment conclusion (after one week of radiation followed by 4 months of chemotherapy). At the treatment conclusion, those deemed to have residual tumor by standard clinical methods (\~65%) will proceed to surgery. For the remaining 35% of patients, with no evidence of active disease, surveillance will be initiated. For these patients, serial imaging examinations will be performed every six months (coordinated with standard examinations). Patients deemed to have a recurrence will undergo surgery.
Once every enrolled patient has completed either surgery or two years of surveillance, the participants will be divided into two groups: Group A (those who underwent surgery) and Group B (those treated solely with nonoperative surveillance). As the primary outcome, Group A will demonstrate the accuracy of photoacoustic imaging. As a secondary outcome, Group A will reveal how the tumor vasculature and %sO2 changes over time, which may provide new insight into how complete response patients respond differently from non-pCR patients and how PAM/US can capture these earlier changes. The investigators will follow up on their SOC results in the clinical system and correlate their PAM/US results during the 2-year surveillance with their five-year disease-free survival.
To identify each patient as a complete or non-complete responder, the investigators will analyze photoacoustic images of all group #2 56 patients serially with the reader team assisted by deep learning algorithms developed earlier in the trial. These quantitative measures, as well as any qualitative local vasculature and %sO2 changes and US morphological changes, will be recorded at each time point. Standard MRI and endoscopic images will be independently collected and analyzed.
As a final part of this trial, the investigators will explore patterns of post-treatment vascular and %sO2 changes during preoperative treatment and serial surveillance. Tumor angiogenesis in colorectal cancer has been well studied using microvessel density (MVD) as a surrogate marker. While high levels of MVD and vascular endothelial growth factor (VEGF) significantly predict poor survival, little is known about the dynamics of vascular and %sO2 changes and the mechanisms of neovascularization after chemoradiation.
The investigators have observed tumor beds revert from oncologically-disrupted microvascular patterns to highly regular architecture typical of the normal rectum where pCR has occurred, though this mechanism is not well-understood. In contrast, heterogeneous and often microvascular-deficient regions have been found consistently in tumor beds with residual cancer at treatment completion. This novel imaging device could serve as a new platform for investigating the dynamics of vascular and %sO2 changes during and after therapy and for assessing potential rectal cancer recurrence early on. In addition to PAM/US imaging studies, the surgeon will perform biopsies at the central region and edges of the tumor bed before treatment, at treatment completion (if no surgery), and at the point of tumor reoccurrence. For patients with surgery, surgical samples will be used. Specifically, MVD and VEGF expression will be assessed by immunohistochemical staining, and both will be quantitatively correlated with PAM/US findings at the center of the tumor bed and at the tumor edges. The results will help the investigators understand how vasculature changes during treatment and at recurrence are correlated with imaging findings.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 90
- Patients with any stage of rectal cancer undergoing surgical resection and the 3 surgeons and 1 radiologist as part of the reader team who diagnose the images obtained in these patients using the PAM/US probe.
- Age >18 years
- Able to provide informed consent
Additional Inclusion Criterion for in vivo imaging
- In patients: Lesion located within 15cm of the anal verge
- In patients: Inability to provide consent
- In patients: Collection of intraoperative specimen for frozen section analysis will disqualify patients from participation
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ex vivo imaging Photoacoustic imaging, photoacoustic microscopy * Patients with known adenomatous polyps or malignancies in the colon or rectum undergoing resection will be considered for enrollment * Participation will include imaging of both normal and known pathologic portions of the specimen ex vivo immediately following resection. The specimen will then undergo fixation and standard pathologic evaluation, with subsequent correlation between imaging and pathologic findings. * This data will also be used to develop a convolutional neural network (CNN) to assist in interpreting photoacoustic imaging data. In vivo imaging Photoacoustic imaging, photoacoustic microscopy * Patients with distal rectal lesions (benign or malignant tumors within 15cm of the anal verge) will be enrolled for the in vivo imaging portion of the study * Participation will include an intraoperative, in vivo evaluation of the tumor with a novel endorectal photoacoustic ultrasound probe as well as ex vivo imaging post-resection as described above. Following the induction of anesthesia, patients will undergo a 20 minute endorectal imaging evaluation performed by their colorectal surgeon. After imaging, the patient will then undergo standard-of-care surgical resection of the rectum. The resection specimen will then be imaged ex vivo as performed in the "ex vivo cohort" of this study. * For this portion of the pilot, enrollment will be limited to 40 participants Ex vivo imaging Endorectal photoacoustic imaging probe * Patients with known adenomatous polyps or malignancies in the colon or rectum undergoing resection will be considered for enrollment * Participation will include imaging of both normal and known pathologic portions of the specimen ex vivo immediately following resection. The specimen will then undergo fixation and standard pathologic evaluation, with subsequent correlation between imaging and pathologic findings. * This data will also be used to develop a convolutional neural network (CNN) to assist in interpreting photoacoustic imaging data. In vivo imaging Endorectal photoacoustic imaging probe * Patients with distal rectal lesions (benign or malignant tumors within 15cm of the anal verge) will be enrolled for the in vivo imaging portion of the study * Participation will include an intraoperative, in vivo evaluation of the tumor with a novel endorectal photoacoustic ultrasound probe as well as ex vivo imaging post-resection as described above. Following the induction of anesthesia, patients will undergo a 20 minute endorectal imaging evaluation performed by their colorectal surgeon. After imaging, the patient will then undergo standard-of-care surgical resection of the rectum. The resection specimen will then be imaged ex vivo as performed in the "ex vivo cohort" of this study. * For this portion of the pilot, enrollment will be limited to 40 participants
- Primary Outcome Measures
Name Time Method Sensitivity and Specificity of the diagnosis by reader team assisted by PAM/US-CNNs Approximately 30 minutes The primary endpoint is to see if the Readers trained to use the co-registered probe are able to diagnose rectal cancers in images obtained from in vivo patients with better sensitivity \& specificity with PAM/US compared to MRI/DWI and other clinical findings. The specificity in the patients under the reader team assisted by PAM/US-CNNs measures the probability of being classified as a responder by the reader team for a pCR. The sensitivity in the surgery patients under the reader team assisted by PAM/US-CNNs measures the probability of being classified as a non-responder by the reader team assisted by PAM/US-CNNs for a non-pCR. High sensitivity also suggests a low chance of classifying a non-pCR as a PAM/US responder. Without compromising cancer detection sensitivity, the investigators seek to assess the ability of PAM/US to potentially reduce surgeries on pCR \& near pCR patients. The analysis includes all with non-cCR outcomes from the SOC \& the reader team assisted by PAM/US-CNNs.
- Secondary Outcome Measures
Name Time Method Performance characteristics of the novel endorectal ultrasound probe as measured by time required to complete study Approximately 30 minutes Performance characteristics of the novel endorectal ultrasound probe as measured by variability in image production Approximately 30 minutes Area under the receiver operating curve (ROC) Approximately 30 minutes The secondary outcome is the accuracy of co-registered PAM/US in assisting surgeons on risk management and surgery recommendation by measuring the area under the receiver operating curve (AUC) in a cohort of patients with the designed statistical power given in the power analysis.
Characterize in vivo tissue samples with photoacoustic imaging Approximately 30 minutes This outcome will be measured qualitatively by comparing histologic (ex vivo) findings to the experimental imaging. The critical features to be analyzed in each image are the cross-sectional structure of normal colorectal tissues in comparison to the loss of a layered structure and its corresponding evenly distributed vascular pattern in the setting of neoplasia.
Performance characteristics of the novel endorectal ultrasound probe as measured by number of adverse events Approximately 30 minutes Performance characteristics of the novel endorectal ultrasound probe as measured by evidence of tissue damage from the imaging laser Approximately 30 minutes
Trial Locations
- Locations (1)
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States